BACKGROUND Gastric cancer is one of the most common cancers worldwide, with a 5-year survival rate of only 20%. The age of onset of gastric cancer is in line with the general rule of cancer. Most of them occur after middle age, mostly between 40 and 60 years old, with an average age of about 50 years old, and only 5% of patients are under 30 years old. The incidence of male is higher than that of female. AIM To investigate the short-term efficacy and influencing factors of chemotherapy combined with irinotecan in patients with advanced gastric cancer. METHODS Eighty patients with advanced gastric cancer who were treated in our hospital from January 2019 to January 2022 were selected. The patients were divided into an observation group ( n = 40) and control group ( n = 40) by the envelope method. The control group was given preoperative routine chemotherapy. The observation group was treated with irinotecan in addition to the chemotherapy given to the control group. The short-term efficacy of treatment in the two groups, as well as tumor marker levels and quality of life before and after treatment were evaluated. RESULTS The short-term treatment effect in the observation group was better than that in the control group ( P < 0.05), and the total effective rate was 57.50%. The age and proportion of tumor node metastasis (TNM) stage IV patients with ineffective chemotherapy in the observation group were (65.12 ± 5.71) years and 52.94%, respectively, which were notably higher than those of patients with effective chemotherapy ( P < 0.05), while the Karnofsky Performance Scale score was (67.70 ± 3.83) points, which was apparently lower than that of patients with effective chemotherapy ( P < 0.05). After 3 mo of treatment, the SF-36 scale scores of physiological function, energy, emotional function, and mental health in the observation group were 65.12 ± 8.14, 54.76 ± 6.70, 47.58 ± 7.22, and 66.16 ± 8.11 points, respectively, which were considerably higher than those in the control group ( P < 0.05). The incidence rates of grade III-IV diarrhea and grade III-IV thrombocytopenia in the observation group were 32.50% and 25.00%, respectively, which were markedly higher than those in the control group ( P < 0.05). CONCLUSION Chemotherapy combined with irinotecan in patients with advanced gastric cancer has a good short-term efficacy and can significantly reduce serum tumor markers and improve the quality of life of patients. The efficacy may be affected by the age and TNM stage of the patients, and its long-term efficacy needs further study.